Bone is an organ whose multiple functions of weight-bearing, ionic regulation, and hematopoiesis necessitate intricate communication between bone cells and coordination between bone formation and turnover. Inappropriate regulation in this complex interactive network can distort this normal homeostasis, resulting in various pathological conditions. Inflammation is a common complication of many diseases and is associated with alterated local signals and increased bone degradation in such conditions as periodontal disease and some forms of arthritis. The recruitment, differentiation, and biological actions of bone cells is governed by cell interactions and a wide array of systemic and local mediators. Osteoblasts, osteoclasts, marrow stromal cells, and vascular endothelial cells are among the bone cells known to produce and respond to such local modulators, including inflammatory mediators. Recently, a new locally produced and acting signal molecule has been described that functions as a sensitive intercellular communication signal in numerous tissues. This transient messenger, the free radical nitric oxide, acts in neurotransmission, vascular signalling the vessel tone, platelet function and blood clotting, macrophage immune cytotoxicity, and brain synaptic plasticity, and has been implicated in the development of arthritis, autoimmunity, periodontal disease, AIDS, and other inflammatory diseases. In bone, nitric oxide elicits osteoclast shape changes and inhibits bone resorption. Other actions of nitric oxide within bone have not yet been investigated, nor is much known regarding its potential origin(s) and regulation. The studies proposed here are designed to test the hypothesis that osteoblasts may respond to modulatory levels of nitric oxide and perhaps also serve as a source for this messenger molecule. Furthermore, osteoblast exposure to modulators of nitric oxide or inflammatory agents may alter their release or response to nitric oxide, and consequently, modify osteoblast/osteoclast interactions. Changes in characteristic osteoblast properties after modulator treatment will be investigated using primary osteoblasts, marrow stromal cells, and transformed cell lines. In other experiments, treated osteoblasts will be cocultured in transwells with osteoclasts or their progenitor cells (marrow mononuclear cells) to analyze the effects that modulating the nitric oxide system in osteoblasts has on their regulation of osteoclast development and resorption capability. These studies will help to define the network of nitric oxide communication within bone, its relationship to inflammation, and ultimately, should broaden our understanding of normal and pathological bone processes.